Type XVIII collagen, a member of the multiplexin subfamily of collagens, is a proteoglycan composed largely of heparan sulfate side chains (Halfter et al., (1998) J. Biol. Chem. 273:25404-12). It is localized mainly in the perivascular regions around the blood vessels in the intestinal villi, choroids plexus, skin, liver and kidneys, and is present in adult and embryonic basal laminae (Kreuger et al., (2002) EMBO J. 21:6303-11). In ocular tissues, type XVIII collagen has been shown to be present in the retinal basal lamina, pigment epithelial basement lamina and periocular mesenchyme (Halfter et al., (1998) supra), as well as in the corneal epithelial basement membrane and in the stromal side of Descemet's membrane. Incisional wounds in mouse corneal tissue result in enhanced collagen XVIII mRNA and protein expression along the wound edges (Lin et al., (2001) Invest. Ophthalmol. Vis. Sci. 42:2517-24; Kure et al., (2001) FEBS Lett. 508:187-90).
In vitro studies have shown that the hinge domain of type XVIII collagen, located between the association domain and the endostatin domain, is cleaved by proteases including elastase and/or cathepsin L to release endostatin, a 20 kDa peptide, from the carboxyl terminal of type XVIII collagen (Sasaki et al. (1998) EMBO J. 17:4249-56; Wen et al., (1999) Cancer Res. 59:6052-6; Felbor et al., (2000) EMBO J. 19:1187-94; Ferreras et al., (2000) FEBS Lett. 486:247-51).
Endostatin, has tumor-suppressing properties and potent anti-angiogenic activity (O'Reilly et al., (1997) Cell 88:277-85). Endostatin has been shown to inhibit cell migration, cell proliferation, decrease tumor size and enhance vascular endothelial cell apoptosis in vitro and in vivo (Chang et al., (2001) Curr. Opin. Ophthalmol. 12:242-9; Colorado et al., (2000) Cancer Res. 60:2520-6; Marneros and Olsen, (2001) Matrix Biol. 20:337-45; Shichiri and Hirata, (2001) FASEB J. 15:1044-53). The mechanisms operative in the effect of endostatin on vascular endothelial cells have been intensively investigated and several endostatin-associated molecules have been isolated and characterized, including matrix metalloproteinase-2, integrin αVβ3, VEGF receptor (KDR/flk-1), tropomyosin, glypican and laminin (Lee et al., (2002) FEBS Lett. 519:147-52; Rehn et al., (2001) Proc. Natl. Acad. Sci. USA 98:1024-9; Kim et al., (2000) Cancer Res. 60:5410-3; Kim et al., (2002) J. Biol. Chem. 277:27872-9; Javaherian et al., (2002) J. Biol. Chem. 277:45211-8). Endostatin binding to these cellular counterparts may facilitate the function of endostatin in vascular endothelial cell proliferation.